Type II TGF Beta Receptor and RCC Progression

描述（由申请人提供）：肾细胞癌（RCC）的发病率在过去三十年中稳步上升，其中局部肿瘤的发病率增幅最大。迄今为止，治疗局限性肾细胞癌的主要方法仍然是手术切除。不幸的是，尽管进行了积极的手术治疗，但超过30%的手术时没有转移证据的RCC患者随后会发生远处转移（即疾病进展），其中大约三分之二的患者会在手术后一年内发生转移。因此，肾癌研究中一个重要且有争议的问题是确定与局部疾病手术后进展风险相关的预后因素。虽然一些研究人员最近发表了预测RCC进展风险的复杂评分算法，但这些算法完全基于临床和病理指标。因此，它们仅代表了决定肿瘤侵袭性的潜在分子特征的替代措施，因此它们本身并不能提供治疗干预的潜在靶点。这一局限性强调了明确需要识别分子预后因素，这些因素不仅有可能改善RCC进展的预测，而且还可能为临床干预提供潜在的目标。最近，我们研究小组的成员发表了令人信服的基因组阵列数据，表明II型转化生长因子β受体（TbetaR2）的表达缺失是RCC获得转移表型的一个重要事件。此外，这些阵列数据已经过验证（实时PCR，免疫组织化学，小鼠模型），并与其他先前的研究一致，这些研究也表明TbetaR2的丢失是RCC进展中的重要事件。在这项研究中，我们建议将这些令人信服的实验室数据转化为临床人群，在2000年1月1日至2003年12月31日期间在罗切斯特梅奥诊所接受手术治疗的369例局部RCC患者中，通过确定TbetaR2表达是否与RCC进展相关。明确地，我们将在单变量和多变量环境中检验较低的TbetaR2表达与RCC进展风险增加相关的假设。作为二次分析的一部分，我们还将研究在我们的基因组分析研究中也被鉴定为异常调节的5个TbetaR2信号下游靶点的表达作用。总之，我们将评估关于RCC进展的分子决定因素的创新翻译假设，以便更好地了解这种疾病的发病机制，并可能为新的治疗方案提供信息。

DESCRIPTION (provided by applicant): Incidence rates for renal cell carcinoma (RCC) have risen steadily over the past three decades with the greatest increases reported for localized tumors. To date, the mainstay of treatment for patients with localized RCC remains surgical excision. Unfortunately, despite aggressive surgical therapy, over 30% of RCC patients with no evidence of metastasis at time of surgery will subsequently develop distant metastases (i.e. disease progression) and roughly two-thirds of those will occur within the first year after surgery. Therefore, an important and controversial issue in renal cancer research is the identification of prognostic factors that correlate with risk of progression following surgery for localized disease. While some investigators have recently published sophisticated scoring algorithms that predict risk of RCC progression, these algorithms are based entirely on clinical and pathologic indices. As such, they represent only surrogate measures for the underlying molecular characteristics that determine tumor aggressiveness and for that reason themselves do not provide potential targets for therapeutic intervention. This limitation underscores a clear need to identify molecular prognostic factors that have the potential to not only improve prediction of RCC progression but also provide potential targets for clinical intervention. Recently, members of our investigative team published compelling genomic array data that implicates loss of expression of the type II transforming growth factor beta receptor (TbetaR2) as a significant event in the acquisition of metastatic phenotype for RCC. Moreover, these array data have been validated (real time PCR, immunohistochemistry, mouse model) and are consistent with other previous studies that also suggest loss of TbetaR2 is an important event in RCC progression. In this investigation, we propose to translate these compelling laboratory data to a clinical population by determining if TbetaR2 expression is associated with RCC progression in a cohort of 369 patients treated surgically for localized RCC at the Mayo Clinic Rochester between January 1, 2000 and December 31, 2003. Explicitly, we will test the hypothesis that lower TbetaR2 expression is associated with an increased risk of RCC progression in both a univariate and multivariate setting. As part of our secondary analyses, we will also examine the role of expression of five downstream targets of TbetaR2 signaling that were also identified as aberrantly regulated in our genomic profiling study. In summary, we will evaluate an innovative translational hypothesis regarding molecular determinants of RCC progression in order to better understand the pathogenesis of this disease and potentially inform on novel treatment regimens.